Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring

Cell Metab. 2016 Apr 12;23(4):735-43. doi: 10.1016/j.cmet.2016.01.014. Epub 2016 Feb 18.


Both epidemiologic and experimental animal studies demonstrate that chronic psychological stress exerts adverse effects on the initiation and/or progression of many diseases. However, intergenerational effects of this environmental information remains poorly understood. Here, using a C57BL/6 mouse model of restraint stress, we show that offspring of stressed fathers exhibit hyperglycemia due to enhanced hepatic gluconeogenesis and elevated expression of PEPCK. Mechanistically, we identify an epigenetic alteration at the promoter region of the Sfmbt2 gene, a maternally imprinted polycomb gene, leading to a downregulation of intronic microRNA-466b-3p, which post-transcriptionally inhibits PEPCK expression. Importantly, hyperglycemia in F1 mice is reversed by RU486 treatment in fathers, and dexamethasone administration in F0 mice phenocopies the roles of restraint stress. Thus, we provide evidence showing the effects of paternal psychological stress on the regulation of glucose metabolism in offspring, which may have profound implications for our understanding of health and disease risk inherited from fathers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Methylation
  • Gene Expression Regulation
  • Gluconeogenesis*
  • Hyperglycemia / etiology*
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology
  • Liver / metabolism
  • Liver / physiopathology*
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Promoter Regions, Genetic
  • Repressor Proteins
  • Stress, Psychological / complications*
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Transcription Factors / genetics


  • MicroRNAs
  • Mirn466 microRNA, mouse
  • Repressor Proteins
  • Sfmbt2 protein, mouse
  • Transcription Factors
  • Phosphoenolpyruvate Carboxykinase (ATP)